Do Prostaglandin Analogs Affect Eyelid Position and Motility?

Abstract

Purpose:

The authors aim at investigating the possible clinical effects of topical Prostaglandin Analogs on eyelid position and motility with this single masked protocol in a cross-sectional study.

Methods:

A group (group A) of 182 patients on treatment for glaucoma with prostaglandin analogs (latanoprost, travoprost, and bimatoprost) and a group of 191 age-matched normal controls (group B) were enrolled in the study. Group A was subdivided into 3 subgroups according to the prostaglandin analogs used by the patients. Group A1: 84 patients on latanoprost, group A2: 56 patients on travoprost, and group A3: 42 patients on bimatoprost. Two positive control groups (group H of 115 patients with lower lid involutional entropion or ectropion secondary to horizontal lid laxity (HLL), and a group P of 137 patients with involutive aponeurotic blepharoptosis) were also enrolled in the study. For the upper eyelid, the following parameters were measured: margin-reflex distance (MRD), upper lid crease position, levator function. For the lower lid, the following parameters were used: HLL and lower lid excursion (LLE). Statistical analysis of the data was done to assess whether there was any statistical significant difference for each of the parameter between group A (and its subgroups) and, respectively, groups B, H, and P. Similarly, it was also compared with group B, with group H, and then with group P. Analysis of variance of the eyelid parameters was also carried out in the 3 subgroups A1, A2, and A3.

Results:

There was no statistically significant difference for each studied parameter between group B and, respectively, groups A1, A2, A3 and group A, nor there was any statistically significant variance between parameters in the 3 subgroups A1, A2, and A3. The accuracy of the eyelid parameters was confirmed while obtaining statistically significant differences in LLE (P<0.05) and in HLL (P<0.001) comparing group A (and its subgroups) and group H and also in MRD and upper lid crest (P<0.001) comparing group A (and its subgroups) and group P.

Conclusions:

There is no evidence that prostaglandin analogs significantly affect the eyelids' tissues to produce eyelid malposition.

Introduction

The topical prostaglandin analogs currently used today for glaucoma treatment are latanoprost, travoprost, bimatoprost, and tafluprost. In this study, tafluprost was not considered due to its very recent use for the treatment of glaucoma. Latanoprost and travoprost are derived from a similar basic chemical structure, that of Prostaglandin-F-2 alpha (PGF2α) isopropyil ester, and they reduce the intraocular pressure (IOP) primarily by increasing the uveoscleral outflow interacting mainly with ocular prostaglandin receptors such as the Prostaglandin F (FP) receptors.^1–6 The increased uveoscleral outflow is secondary to the relaxation of the ciliary smooth muscle fibers and lysis of the scleral extracellular matrix (ECM) produced by an increase of matrix metalloproteinases (MMPs).^7–10 Bimatoprost is a prostamide and it increases uveoscleral outflow, reduces episcleral venous pressure, and also causes a tonographic decrease in the resistance to the aqueous humor outflow.^11–13

Many adverse effects have been reported with prostaglandin analogs, including conjunctival hyperemia, iris hyperpigmentation, and eyelash growth.^14–17 Other reported, less-frequent side effects are disruption of the blood-aqueous barrier with development of cystoid macular edema, iritis, and recurrence of herpes simplex keratitis.¹⁴

A case of extensive hair growth¹⁸ in malar region and a case of eyelash ptosis¹⁹ caused by latanoprost therapy have also been recently reported.

The occurrence of dermatologic side effects of bimatoprost 0.03% (changes of length and density of eyelashes, changes of length and density of vellus hair of the malar and external canthal skin regions, and changes in periocular skin pigmentation) are likely to be related to the direct drop-skin contact.²⁰

The eyelids are exposed to high concentrations of topical prostaglandin analogs when used for treatment of glaucoma or ocular hypertension (OHT).^13–19 After MEDLINE computerized research (Search words: Prostaglandin analogs, Eyelid malposition, Blepharoptosis, Eyelid pathology, and Presence of Prostaglandin Analogs in eyelids), we are not aware of reports suggesting that prostaglandin analogs affect connective tissue of the eyelid in a similar fashion to those produced in the scleral ECM and ciliary smooth muscle fibers.

In a study, Mietz²¹ investigated the presence and possible role of different MMPs and their tissue inhibitors (TIMPs) in tenon capsule fibroblasts after treatment with latanoprost both in vivo (using untreated and treated human fibroblasts) and in vitro (using conjunctival specimens of treated rabbits). Mietz found that tenon fibroblasts contain the ability on the mRNA level to synthesize all enzymes of the MMP and TIMP family that are related to remodeling of the ECM, and that the levels of MMP-3 and TIMP-2 increase after treatment with latanoprost.

Although these data are not applicable to the palpebral tissues containing fibroblasts such as tarsus, orbital septum, canthal tendons, upper eyelid levator, and lower eyelid retractors aponeurosis, we designed this study with the aim of assessing whether prostaglandin analogs may clinically affect (in terms of relaxation) the ECM of the above-mentioned palpebral tissues (in a similar way to the tenons fibroblasts and scleral and smooth ciliary muscular tissues) with subsequent pathological changes in eyelids' position and motility.

Methods

All patients and subjects included in the study gave their informed consent before being included in the study. The data collection was performed in accordance with the ethical standards stated in the 1964 Declaration of Helsinki. All patients and normal control subjects gave their signed informed consent before being involved in this study. The study was approved by the Ethics Committee of Hospital of Imperia, Imperia, Italy.

One hundred eighty-two patients (group A) on treatment for primary open angle glaucoma (POAG) or OHT with prostaglandin analogs (subgroup A1: 84 patients on latanoprost, subgroup A2: 56 patients on travoprost and subgroup A3: 42 patients on bimatoprost) and 191 age-matched normal control subjects on no treatment (group B) were consecutively enrolled from our clinics.

Two other positive control groups (group H and P) were also studied as follows.

We enrolled a group (group H) of 115 patients in whom lower eyelid involutional malposition (entropion and ectropion) had been diagnosed due to increased horizontal lid laxity (HLL) and a group (group P) of 137 patients in whom upper eyelid aponeurotic blepharoptosis had been diagnosed.

Inclusion and exclusion criteria are summarized in Table 1.

Table 1.

Inclusion and Exclusion Criteria of Studied Patients and Subjects

Group	Inclusion criteria	Exclusion criteria
A	Caucasian race On treatment with latanoprost, travoprost or bimatoprost	Eyelid disease occurred prior to the treatment with prostaglandin analogs Previous surgery involving the adnexa and the eyeball Strabismus
B	Caucasian race	Previous surgery involving the adnexa and the eyeball Strabismus
H	Caucasian race Increased HLL Lower eyelid involutional Entropion or ectropion	Previous surgery involving the adnexa and the eyeball Strabismus Other causes of entropion and ectropion (cicatricial, congenital)
P	Caucasian race Aponeurotic blepharoptosis	Previous surgery involving the adnexa and the eyeball Strabismus Other causes of blepharoptosis (congenital, myogenic, neurogenic)

HLL, horizontal lid laxity.

Only 1 eye per patient was randomly included in the study for all subjects in group B and for patients treated bilaterally in group A. In groups H and P, the eye affected by the eyelid malposition was included; and where both the eyes were affected, only 1 eye was randomly included.

All patients and subjects were included in the study only by 1 author (E.F.) and, before their inclusion, underwent a complete ophthalmic assessment including biomicroscopy, visual acuity, IOP, motility, and funduscopy.

We define entropion²² as an inward rotation of eyelid margin and ectropion²³ as an outward rotation of eyelid margin. The blepharoptosis²⁴ is a drooping of the upper eyelid.

The definition of POAG and OHT for each patient was done according to European Glaucoma Society guidelines.²⁵ In fact, we define an eye affected by POAG when there is the following: (1) open angle at goniscopy, (2) IOP>21 mmHg on no treatment, (3) no evidence of apparent secondary cause of glaucoma, and (4) typical abnormal optic nerve head and/or typical glaucomatous visual field loss.

We define an eye with OHT when there is the following: (1) open angle at gonioscopy, (2) IOP>21 mmHg on no treatment, and (3) normal optic nerve head and normal visual field.

The normal control group is formed by subjects without any ocular pathology and on no treatment.

The following eyelid parameters were then measured for each studied eye^26–32 of all groups:

Upper eyelid

Margin-reflex distance

Margin-reflex distance (MRD) is the distance from the upper eyelid margin to the corneal light reflex with the eyeball being in primary position (normal value: 4 mm).

Upper lid crease

Upper lid crease (ULC) is the distance from the upper eyelid crease to the eyelid margin. The insertion of the levator aponeurosis into the skin contributes to the formation of the upper eyelid crease. Duplicated and asymmetric creases are related to abnormal insertion or disinsertion of the aponeurosis (normal value between 7 and 12 mm).

Levator function

Levator function (LF) is measured by calculating the upper eyelid excursion from downgaze to upgaze. When the LF is being quantified, frontalis muscle contribution (which may augment the lifting of the ptotic eyelid) should be blocked manually by the examiner's thumb (normal value: 15 mm or higher).

Lower eyelid

Lower lid excursion

Expression of vertical lower lid laxity is measured by placing a small ink reference mark on each lower eyelid margin centered below the pupil. The patient fixates a distant target in primary position. A millimeter ruler was placed vertically against this reference mark to measure eyelid movement vertically. The patient was asked to move his eyes from extreme downgaze to extreme upgaze while holding his head still. The total vertical excursion of the reference mark was then measured.^26–30 As shown by Shore, the normal lower lid excursion (LLE) in normal subjects is supposed to be 5.29 mm with a decrease of 0.05 mm per year.²⁷

Horizontal lid laxity

HLL was assessed by the distraction or pinch test. If the lid margin can be pulled >8 mm away from the eyeball as measured with a caliper, significant laxity is present. The distance between eyeball and eyelid was measured with the caliper. Distance between the 2 tips of the caliper was measured with a ruler calibrated to half a millimeter.^27–31

All eyelid parameters were assessed in all patients and subjects groups, after their enrollment in the study, by the same observer (M.A.), who according to the protocol (single masked protocol) did not know which group the patient or subject belonged to.

Statistical analysis of the collected data was done using the Student's t test when the data distribution was normal. Mann-Whitney test was used when the data distribution was not normal. Both tests were used for calculating any statistical significant difference of the above-mentioned parameters between group B and, respectively, the subgroups A1, A2, A3, and group A.

Then, between group H and, respectively, the subgroups A1, A2, A3, and group A.

Any statistically significant difference of the eyelid parameters between group P and, respectively, the subgroups A1, A2, A3, and group A was also calculated.

Any statistically significant difference of the eyelid parameters between group B and, respectively, the groups H and P was also calculated.

This last comparison between group B, involving normal controls subjects, and groups H and P, where there is a diagnosed eyelid malposition, was done for confirming the adequacy of selected eyelid parameters in this study.

We also performed analysis of variance with the Kruskal-Wallis test for each studied parameter, to assess whether there was any statistically significant variance in the 3 subgroups (A1, A2, and A3).

A P value <0.05 was considered statistically significant for all statistical tests.

Results

One hundred fifty-four patients of group A and 168 subjects of group B matched all inclusion criteria. Demographic data of all groups of patients and normal controls included in the study are summarized in Table 2. The patients of group A had been on prostaglandin analogs for a median time of 1.59±0.83 years (Table 2).

Table 2.

Descriptive Analysis of Enrolled Patients and Subjects

	Group A Total prostaglandin analogs group	Subgroup A 1 Latanoprost	Subgroup A 2 Travoprost	Subgroup A 3 Bimatoprost	Group B Normal age-matched controls group	Group H HLL group	Group P Ptosis group
Total number	154	73	43	38	168	98	112
Males	61	32	18	11	75	26	48
Females	93	41	25	27	93	72	64
Age in years (mean±SD)	79.21±17.93	71.36±20.97	76.91±16.54	73.47±12.56	73.43±15.27	69.45±19.21	78.93±28.11
Treatment length (years±SD)	1.59±0.83	2.57±0.79	1.13±0.39	1.24±0.55	0	0	0

SD, standard deviation.

Subgroup A1 involved 73 patients on latanoprost, subgroup A2 involved 43 patients on travoprost and subgroup A3 involved 38 patients on bimatoprost.

In group A, we detected 9 cases of eyelid disorders that occurred in the included eye: 6 cases of significant HLL (4 involutional lower eyelid ectropion and 2 involutional lower eyelid entropion), and 3 cases of aponeurotic blepharoptosis with good levator muscle function (Table 3).

Table 3.

Eyelid Disorders Occurred During Prostaglandin Analogs Therapy in Included Patients

Ptosis
Number of cases	Treatment duration (prostaglandin analogs) in months±SD	LF (mm±SD)
3	10.75±5.78	17.31±1.52

Entropion
Number of cases	Treatment duration (prostaglandin analogs) in months±SD	HLL (mm±SD)
2	9.78±6.93	9.03±1.34

Ectropion
Number of cases	Treatment duration (prostaglandin analogs) in months±SD	HLL (mm±SD)
4	8.25±2.68	8.59±2.62

LF, levator function.

The eyelid disorders in all cases were not present before start the antiglaucoma treatment with prostaglandin analogs, and they occurred after a variable time of prostaglandin analogs assumption (Table 3). In all cases, the disorder was unilateral.

Ninety-eight patients of group H and 112 patients of group P matched all inclusion criteria and so were enrolled in the study. These patient groups are positive control groups, that is, patient groups with an involutional age-related eyelid malposition (involutional entropion or ectropion in group H, aponeurotic blepharoptosis in group P).

The data distribution in all groups was not normal (i.e., not gaussian), so we used the Mann-Whitney test for studying the differences of the eyelid parameters between the different groups.

No statistically significant differences for the studied parameters (MRD, ULC, LF, LLE, and HLL) between group B and the other subgroups (A1, A2, and A3) and between group B and group A were found (P>0.05).

After comparing group A (and A1, A2, A3) and group H, we found statistically significant differences between LLE (P<0.05) and HLL (P<0.001).

Comparing group A (and A1, A2, A3) and group P, we found statistically significant differences between MRD and ULC (P<0.001). Comparing the eyelid parameters between group B and group H, we found statistically significant differences between LLE (P<0.05) and HLL (P<0.001). Comparing finally the eyelids parameters between group B and group P, we found statistically significant differences between MRD and ULC (P<0.001).

All the above-mentioned eyelid parameters if all groups and subgroups are summarized in Table 4. At the end, the Kruskall-Wallis test was used for the analysis of variance of the above-mentioned parameters in the 3 subgroups of group A (subgroup A1: latanoprost, subgroup A2: travoprost and subgroup A3: bimatoprost). No statistically significant variance in the 3 subgroups was found (P>0.05). (Table 5).

Table 4.

Results Eyelids Parameters in All Groups and Subgroups

Eyelids parameters (mean in mm±SD)	Group A (total prostaglandin group)	Subgroup A1 (latanoprost)	Subgroup A2 (travoprost)	Subgroup A3 (bimatoprost)	Group B (normal controls)	Group H (positive control group with horizontal lid laxity)	Group P (positive control group with ptosis)
MRD	3.71±0.93	3.54±1.23	3.90±1.04	3.49±0.87	3.95±0.87	3.68±0.53	2.78±0.62
ULC	7.31±1.12	7.23±0.89	7.64±1.43	7.18±1.09	7.84±1.09	7.19±0.87	8.99±1.28
LF	16.21±1.43	17.02±1.12	16.90±1.7	16.98±1.30	15.98±1.74	16.03±1.74	14.06±1.53
LLE	4.63±0.91	4.78±0.64	4.28±0.57	4.93±0.86	4.56±0.75	3.21±0.74	4.98±0.81
HLL	6.25±1.3	6.11±0.91	6.43±0.84	6.32±1.55	6.54±1.41	8.84±1.03	6.21±1.73

MRD, margin reflex distance; ULC, upper lid crease; LLE, lower lid excursion.

Table 5.

Results. Analysis of Variance (Kruskall-Wallis Test)

Eyelids parameters (mean in mm±SD)	Subgroup A1 Latanoprost	Subgroup A2 Travoprost	Subgroup A3 Bimatoprost	P value
MRD	3.54±1.23	3.90±1.04	3.49±0.87	>0.05
ULC	7.23±0.89	7.64±1.43	7.18±1.04	>0.05
LF	17.02±1.12	16.90±1.17	16.98±1.30	>0.05
LLE	4.78±0.64	4.28±0.57	4.28±0.86	>0.05
HLL	6.11±0.91	6.43±0.84	6.43±1.55	>0.05

Discussion

Ophthalmic side effects have been reported after the use of prostaglandin analogs in the treatment of glaucoma. They are rare, and the efficacy and the safety of these agents in the treatment of OHT and glaucoma has been widely proved.^{14–19,33–40} The most important ophthalmic side effects are increase of iris pigmentation (more common in Asian people and remaining unchanged even after discontinuation of therapy), mild conjunctival hyperemia, eyelid dermatitis, corneal punctuate staining, anterior uveitis (granulomatous and not granulomatous), reactivation of herpes-simplex keratitis, and cystoid macular edema in pseudophakic patients (especially after lazer capsulotomy of posterior capsule of the lens bag).^33–41 In a study⁴² the in vitro toxicity of topical ocular prostaglandin analogs and their preservatives on corneal epithelial cells was studied, and Travoprost with SofZia preservative showed the least toxicity.

Honda et al.⁴³ showed that the topical use of latanoprost, due to the increase of MMPs (MMP-1 and MMP-9) and to the decrease of TIMP-1, should not be recommended in patients with keratoconus or after lazer-assisted in situ keratomileusis.

A very curious ophthalmic side effect of prostaglandin analogs is the increase of length and pigmentation of the eyelashes. The molecular mechanism producing those changes is still uncertain.^38–40 This side effect encouraged the use of these agents for the treatment of hypotrichosis of the eyelashes. In fact, Bimatoprost 0.03% (Latisse R) solution was recently approved by the U.S. Food and Drug Administration for increasing eyelash length, thickness, and darkness in patients with hypotrichosis of the eyelashes. When prostaglandin and prostamide analogs interact with the prostanoid receptors in the hair follicle, this most likely stimulates the resting follicles (telogen phase) to growing follicles (anagen phase).⁴⁴ Bimatoprost in gel suspension has similar eyelash-lengthening properties.⁴⁵ On the other hand, Latanoprost did not show any efficacy in the treatment of alopecia areata of eyelashes and eyebrows.⁴⁶

The possible systemic side effects of prostaglandin analogs (even more rare than the ophthalmic ones) are headache, facial rash, and cardiovascular effects.^34–41,47

The etiology of the acquired aponeurotic ptosis, with good LF, is possibly due to the possible disruption of the aponeurotic tissues that produces a dehiscence or a disinsertion of the aponeurosis from the tarsus resulting in aponeurotic ptosis with subsequent alterations of MRD, ULC and generally a good LF.²⁶

In the case of involutional lower lid ectropion and entropion, the increased HLL and vertical lid laxity is the most common etiology of these 2 eyelid malpositions.^28–31 The HLL is related to involutional changes in the tarsal plate and in the orbicularis muscle (canthal tendons stretching expressed by the medial canthal tendon laxity).^27–30 The vertical lid laxity is related to involutional changes described as attenuation, dehiscence, or disinsertion of the lower lid retractors and of the orbital septum and is characterized by an alteration of LLE.^27,31

The ability to synthesize MMPs and TIMPs in palpebral fibrous tissues as Mietz et al.²¹ demonstrated in Tenon's capsule fibroblasts is not proved; and so, we cannot presume any action of prostaglandin analogs in increasing those enzymes that are related to remodeling of the ECM.

In this study, we did not prove any possible clinical action of prostaglandin analogs on the palpebral tissues. In fact, the comparison of the studied lower (HLL and LLE) and upper (MRD, ULC, and LF) eyelid parameters assessed in group A (and separately in subgroups A1, A2, A3) and in group B did not show any statistically significant difference (Table 4).

When we compared the 3 subgroups of the group A, we did not find any statistically significant variance in each of the parameters in the 3 subgroups (Table 5).

The adequacy of selected parameters,^28–32 assessed and compared in the different groups in this study, was confirmed, thus showing their capability of detecting statistically significant changes of LLE and HLL in patients in whom lower eyelid involutional malposition is diagnosed (Table 4), and similarly of detecting statistically significant changes of MRD and ULC in patients in whom aponeurotic blepharoptosis is diagnosed (Table 4).

Conclusions

We did not prove, after our assessments and statistical analysis, any involvement such as a clinically increased laxity or disruption of the eyelid tissues after the use of topical ophthalmic prostaglandin analogs such as latanoprost, travoprost, and bimatoprost. The length of treatment with prostaglandin analogs in the total group A was only a median time of 1.59±0.83 years (Table 3); so, further data after a longer treatment have to be collected and studied.

Although we assessed in our patients groups 6 cases of lower eyelid malposition (4 ectropion and 2 entropion all characterized with increased lower eyelid horizontal laxity) and 3 cases of aponeurotic blepharoptosis, all occurring after a variable length of glaucoma treatment with prostaglandin analogs, we interpretate these occurrences as coincidental and not produced by the effect of these agents on the eyelid tissues.

Finally, the presence of different MMPs and their TIMPs in eyelid's fibroblasts after treatment with prostaglandin analogs both in vivo and in vitro as it was investigated²¹ on the tenon's fibroblasts should be demonstrated.

Footnotes

Acknowledgments

The authors thank Dr. Bimal Kumar, MD, Consultant Ophthalmology and Ophthalmic Plastic Surgeon, Milton Keynes General Hospital, Milton Keynes, Buckinghamshire, United Kingdom, for his important suggestions and assistance.

Author Disclosure Statement

No competing financial interest exist for both authors.

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